Processed Products of Aconitum soongaricum Stapf. Inhibit the Growth of Ovarian Cancer Cells In vivo via Regulating the PI3K/AKT Signal Pathway


Цитировать

Полный текст

Аннотация

Introduction/Objective:The alkaloids of songorine, aconitine, and benzoylaconitine, as the processed products of Aconitum soongaricum Stapf., can significantly inhibit the migration and invasion of ovarian cancer cells in vitro. Herein, we studied the in vivo role and mechanism of these natural products in processed A. soongaricum Stapf.

Methods:A xenograft tumor model was constructed. Tumor volumes and weights were calculated. HE staining assessed the histopathological changes of tumors. Inflammatory factors were detected using ELISA. Gene and protein expressions of E-cadherin, N-cadherin, PIK3CA, and AKT1 proteins were measured using RT-qPCR and immunohistochemistry. Protein expressions of E-cadherin, N-cadherin, PIK3CA, AKT1, p-PIK3CA, and p- AKT1 proteins were detected using western blot analysis.

Results:Songorine, aconitine, and benzoylaconine significantly inhibited the growth of tumors as evidenced by decreased tumor volume and weight. The extent and scope of tumor cell necrosis were less in the songorine group compared to the vehicle group. Songorine, aconitine, and benzoylaconine significantly reduced IL-6, IL-1β, and TNF-α levels. Furthermore, songorine, aconitine, and benzoylecgonine induced down-regulation of N-cadherin and AKT1 mRNA in comparison to the vehicle group. Meanwhile, songorine, aconitine, and benzoylaconine also significantly reduced N-cadherin, p-PIK3CA, and p-AKT1 proteins, while upregulating E-cadherin protein expression in comparison to the vehicle group. These effects were further enhanced when combined with the PI3K inhibitor LY294002.

Conclusion:Songorine, aconitine, and benzoylaconine may inhibit ovarian cancer growth in vivo by blocking the PI3K/AKT signaling pathway. Our findings may provide evidence for the clinical application of the processed products of Aconitum soongaricum Stapf. in ovarian cancer treatment.

Об авторах

Xiaojuan Li

, Pharmacy Department of Fourth Clinical Medical College of Xinjiang Medical University

Email: info@benthamscience.net

Xinle Tang

, Laboratory Department of the Sixth Affiliated Hospital of Xinjiang Medical University

Email: info@benthamscience.net

Liang Chen

, Pharmacy Department of Affiliated Traditional Chinese Medicine Hospital of Xinjiang Medical University

Email: info@benthamscience.net

Xingxing Cao

, Pharmacy Department of Fourth Clinical Medical College of Xinjiang Medical University

Email: info@benthamscience.net

Reziya Ailimujiang

, Pharmacy Department of Fourth Clinical Medical College of Xinjiang Medical University

Email: info@benthamscience.net

Qian Li

, Pharmacy Department of Affiliated Traditional Chinese Medicine Hospital of Xinjiang Medical University

Автор, ответственный за переписку.
Email: info@benthamscience.net

Feicui Zhao

, Pharmacy Department of Affiliated Traditional Chinese Medicine Hospital of Xinjiang Medical University

Автор, ответственный за переписку.
Email: info@benthamscience.net

Список литературы

  1. Yang, C.; Xia, B.R.; Zhang, Z.C.; Zhang, Y.J.; Lou, G.; Jin, W.L. Immunotherapy for ovarian cancer: Adjuvant, combination, and neoadjuvant. Front. Immunol., 2020, 11, 577869. doi: 10.3389/fimmu.2020.577869 PMID: 33123161
  2. Lheureux, S.; Braunstein, M.; Oza, A.M. Epithelial ovarian cancer: Evolution of management in the era of precision medicine. CA Cancer J. Clin., 2019, 69(4), 280-304. doi: 10.3322/caac.21559 PMID: 31099893
  3. Siminiak, N.; Czepczyński, R.; Zaborowski, M.P.; Iżycki, D. Immunotherapy in ovarian cancer. Arch. Immunol. Ther. Exp., 2022, 70(1), 19. doi: 10.1007/s00005-022-00655-8 PMID: 35941287
  4. Yang, L.; Xie, H.J.; Li, Y.Y.; Wang, X.; Liu, X.X.; Mai, J. Molecular mechanisms of platinum‑based chemotherapy resistance in ovarian cancer (Review). Oncol. Rep., 2022, 47(4), 82. doi: 10.3892/or.2022.8293 PMID: 35211759
  5. Moufarrij, S.; Dandapani, M.; Arthofer, E.; Gomez, S.; Srivastava, A.; Lopez-Acevedo, M.; Villagra, A.; Chiappinelli, K.B. Epigenetic therapy for ovarian cancer: Promise and progress. Clin. Epigenetics, 2019, 11(1), 7. doi: 10.1186/s13148-018-0602-0 PMID: 30646939
  6. Zhang, J.; Chen, Y.; Chen, X.; Zhang, W.; Zhao, L.; Weng, L.; Tian, H.; Wu, Z.; Tan, X.; Ge, X.; Wang, P.; Fang, L. Deubiquitinase USP35 restrains STING-mediated interferon signaling in ovarian cancer. Cell Death Differ., 2021, 28(1), 139-155. doi: 10.1038/s41418-020-0588-y PMID: 32678307
  7. Yu, H.H.; Li, M.; Li, Y.B.; Lei, B.B.; Yuan, X.; Xing, X.K.; Xie, Y.F.; Wang, M.; Wang, L.; Yang, H.J.; Feng, Z.W.; Cheng, B.F. Benzoylaconitine inhibits production of IL-6 and IL-8 via MAPK, Akt, NF-κB signaling in IL-1β-induced human synovial cells. Biol. Pharm. Bull., 2020, 43(2), 334-339. doi: 10.1248/bpb.b19-00719 PMID: 31735734
  8. Fu, L.; Dai, L.L.; Zhao, F.C.; Jiang, T. Study on the hydrolysis mechanism of Aconitum soongaricum Stapf. alkaloids and deoxyaconitine. Chin. Tradit. Herbal Drugs, 2018, 49, 5794-5802.
  9. Zhang, L.; Siyiti, M.; Zhang, J.; Yao, M.; Zhao, F. Anti‑inflammatory and anti‑rheumatic activities in vitro of alkaloids separated from Aconitum soongoricum Stapf. Exp. Ther. Med., 2021, 21(5), 493. doi: 10.3892/etm.2021.9924 PMID: 33791002
  10. Mukadais, S. Screening of anti-egfr active components in aconitum ungernii from junggar, xinjiang based on cell membrane chromatography. Chinese Pharmacist, 2018, 21(05), 766-771.
  11. Zhang, L. Study on the anti-tumor activity of alkaloids and processed hydrolysis products of Aconitum soongaricum in Junggar; Xinjiang Medical University: Xinjiang, 2019.
  12. Yang, M. Mechanism research on the inhibitory effects of processed products of Aconitum soongaricum Stapf. on ovarian cancer metastasis and invasion based on network pharmacology and experimental verification; Xinjiang Medical University, 2022.
  13. Wang, Y.; Li, Y.; Wang, L.; Chen, B.; Zhu, M.; Ma, C.; Mu, C.; Tao, A.; Li, S.; Luo, L.; Ma, P.; Ji, S.; Lan, T. Cinnamaldehyde suppressed EGF-induced EMT process and inhibits ovarian cancer progression through PI3K/AKT pathway. Front. Pharmacol., 2022, 13, 779608. doi: 10.3389/fphar.2022.779608 PMID: 35645793
  14. Cui, P.; Li, H.; Wang, C.; Liu, Y.; Zhang, M.; Yin, Y.; Sun, Z.; Wang, Y.; Chen, X. UBE2T regulates epithelial–mesenchymal transition through the PI3K-AKT pathway and plays a carcinogenic role in ovarian cancer. J. Ovarian Res., 2022, 15(1), 103. doi: 10.1186/s13048-022-01034-9 PMID: 36088429
  15. Huang, Y.; Hong, W.; Wei, X. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J. Hematol. Oncol., 2022, 15(1), 129. doi: 10.1186/s13045-022-01347-8 PMID: 36076302
  16. Wu, X.; Zhao, J.; Ruan, Y.; Sun, L.; Xu, C.; Jiang, H. Sialyltransferase ST3GAL1 promotes cell migration, invasion, and TGF-β1-induced EMT and confers paclitaxel resistance in ovarian cancer. Cell Death Dis., 2018, 9(11), 1102. doi: 10.1038/s41419-018-1101-0 PMID: 30375371
  17. Wang, H.; Xu, Y.; Guo, Y. Novel prognostic marker TGFBI affects the migration and invasion function of ovarian cancer cells and activates the integrin αvβ3-PI3K-Akt signaling pathway. J. Ovarian Res., 2024, 17(1), 50. doi: 10.1186/s13048-024-01377-5 PMID: 38395907
  18. Li, D.; Pan, Y.; Huang, Y.; Zhang, P.; Fang, X. PAK5 induces EMT and promotes cell migration and invasion by activating the PI3K/AKT pathway in ovarian cancer. Anal. Cell. Pathol., 2018, 2018, 1-9. doi: 10.1155/2018/8073124 PMID: 30245957
  19. Liu, S.Y.; Chen, W.; Chughtai, E.A.; Qiao, Z.; Jiang, J.T.; Li, S.M.; Zhang, W.; Zhang, J. PIK3CA gene mutations in Northwest Chinese esophageal squamous cell carcinoma. World J. Gastroenterol., 2017, 23(14), 2585-2591. doi: 10.3748/wjg.v23.i14.2585 PMID: 28465643
  20. Cheng, J.C.; Leung, P.C.K. Type I collagen down-regulates E-cadherin expression by increasing PI3KCA in cancer cells. Cancer Lett., 2011, 304(2), 107-116. doi: 10.1016/j.canlet.2011.02.008 PMID: 21377268
  21. Wang, X.; Xu, X.; Jiang, G.; Zhang, C.; Liu, L.; Kang, J.; Wang, J.; Owusu, L.; Zhou, L.; Zhang, L.; Li, W. Dihydrotanshinone I inhibits ovarian cancer cell proliferation and migration by transcriptional repression of PIK3CA gene. J. Cell. Mol. Med., 2020, 24(19), 11177-11187. doi: 10.1111/jcmm.15660 PMID: 32860347
  22. Geng, Y.; Wu, W.; Zhou, L.; Li, J.; Geng, Y.; Yang, Y. Synergistic effects of LY294002 and ABT199 on the cell cycle in K562, HL60 and KG1a cells. Oncol. Rep., 2021, 45(6), 97. doi: 10.3892/or.2021.8048 PMID: 33846811
  23. Xu, R.; Zhang, Y.; Li, A.; Ma, Y.; Cai, W.; Song, L.; Xie, Y.; Zhou, S.; Cao, W.; Tang, X. LY‑294002 enhances the chemosensitivity of liver cancer to oxaliplatin by blocking the PI3K/AKT/HIF‑1α pathway. Mol. Med. Rep., 2021, 24(1), 508. doi: 10.3892/mmr.2021.12147 PMID: 33982772
  24. Jiang, T. Changes in the content of four alkaloids in the processing of Aconitum Ungernii. Zhongchengyao, 2016, 38, 2641-2646.
  25. Wang, X.; Lin, Y.; Zheng, Y. Antitumor effects of aconitine in A2780 cells via estrogen receptor β‑mediated apoptosis, DNA damage and migration. Mol. Med. Rep., 2020, 22(3), 2318-2328. doi: 10.3892/mmr.2020.11322 PMID: 32705198
  26. Zhang, H.; Dong, R.; Zhang, P.; Wang, Y. Songorine suppresses cell growth and metastasis in epithelial ovarian cancer via the Bcl‑2/Bax and GSK3β/β‑catenin signaling pathways. Oncol. Rep., 2019, 41(5), 3069-3079. doi: 10.3892/or.2019.7070 PMID: 30896826
  27. Tao, H.; Liu, X.; Tian, R.; Liu, Y.; Zeng, Y.; Meng, X.; Zhang, Y. A review: Pharmacokinetics and pharmacology of aminoalcohol-diterpenoid alkaloids from Aconitum species. J. Ethnopharmacol., 2023, 301, 115726. doi: 10.1016/j.jep.2022.115726 PMID: 36183950
  28. Vahedian-Movahed, H.; Saberi, M.R.; Chamani, J. Comparison of binding interactions of lomefloxacin to serum albumin and serum transferrin by resonance light scattering and fluorescence quenching methods. J. Biomol. Struct. Dyn., 2011, 28(4), 483-502. doi: 10.1080/07391102.2011.10508590 PMID: 21142219
  29. Azzalini, E.; Barbazza, R.; Stanta, G.; Giorda, G.; Bortot, L.; Bartoletti, M.; Puglisi, F.; Canzonieri, V.; Bonin, S. Histological patterns and intra-tumor heterogeneity as prognostication tools in high grade serous ovarian cancers. Gynecol. Oncol., 2021, 163(3), 498-505. doi: 10.1016/j.ygyno.2021.09.012 PMID: 34602289
  30. Rong, C.; Shi, Y.; Huang, J.; Wang, X.; Shimizu, R.; Mori, Y.; Murai, A.; Liang, J. The effect of metadherin on NF-κB activation and downstream genes in ovarian cancer. Cell Transplant., 2020, 29 doi: 10.1177/0963689720905506 PMID: 32207338
  31. Sommerfeld, L.; Finkernagel, F.; Jansen, J.M.; Wagner, U.; Nist, A.; Stiewe, T.; Müller-Brüsselbach, S.; Sokol, A.M.; Graumann, J.; Reinartz, S.; Müller, R. The multicellular signalling network of ovarian cancer metastases. Clin. Transl. Med., 2021, 11(11), e633. doi: 10.1002/ctm2.633 PMID: 34841720
  32. Shi, J.; Huo, R.; Li, N.; Li, H.; Zhai, T.; Li, H.; Shen, B.; Ye, J.; Fu, R.; Di, W. CYR61, a potential biomarker of tumor inflammatory response in epithelial ovarian cancer microenvironment of tumor progress. BMC Cancer, 2019, 19(1), 1140. doi: 10.1186/s12885-019-6321-x PMID: 31766991
  33. Liu, J.; Li, L.; Luo, N.; Liu, Q.; Liu, L.; Chen, D.; Cheng, Z.; Xi, X. Inflammatory signals induce MUC16 expression in ovarian cancer cells via NF‑κB activation. Exp. Ther. Med., 2020, 21(2), 163. doi: 10.3892/etm.2020.9594 PMID: 33456530
  34. Jo, E.; Jang, H.J.; Yang, K.E.; Jang, M.S.; Huh, Y.H.; Yoo, H.S.; Park, J.S.; Jang, I.S.; Park, S.J. Cordyceps militaris induces apoptosis in ovarian cancer cells through TNF-α/TNFR1-mediated inhibition of NF-κB phosphorylation. BMC Complement. Med. Ther., 2020, 20(1), 1. doi: 10.1186/s12906-019-2780-5 PMID: 32020859
  35. Liu, C.; Huang, X.; Su, H. The role of the inflammasome and its related pathways in ovarian cancer. Clin. Transl. Oncol., 2022, 24(8), 1470-1477. doi: 10.1007/s12094-022-02805-y PMID: 35288840
  36. Gening, S.O.; Abakumova, T.V.; Antoneeva, I.I.; Rizvanov, A.A.; Gening, T.P.; Gafurbaeva, D.U. Stem-like tumor cells and proinflammatory cytokines in the ascitic fluid of ovarian cancer patients. Russ. Clin. Lab. Diagn., 2021, 66(5), 297-303. doi: 10.51620/0869-2084-2021-66-5-297-303 PMID: 34047516
  37. Mao, T.L.; Fan, M.H.; Dlamini, N.; Liu, C.L. LncRNA MALAT1 facilitates ovarian cancer progression through promoting chemoresistance and invasiveness in the tumor microenvironment. Int. J. Mol. Sci., 2021, 22(19), 10201. doi: 10.3390/ijms221910201 PMID: 34638541
  38. Wang, D.; Zhang, L.; Hu, A.; Wang, Y.; Liu, Y.; Yang, J.; Du, N.; An, X.; Wu, C.; Liu, C. Loss of 4.1N in epithelial ovarian cancer results in EMT and matrix-detached cell death resistance. Protein Cell, 2021, 12(2), 107-127. doi: 10.1007/s13238-020-00723-9 PMID: 32448967
  39. Fan, L.; Lei, H.; Zhang, S.; Peng, Y.; Fu, C.; Shu, G.; Yin, G. Non-canonical signaling pathway of SNAI2 induces EMT in ovarian cancer cells by suppressing miR-222-3p transcription and upregulating PDCD10. Theranostics, 2020, 10(13), 5895-5913. doi: 10.7150/thno.43198 PMID: 32483426
  40. Augustine, D.; Khan, W.; Rao, R.; Patil, S.; Awan, K.; Sowmya, S.; Haragannavar, V.; Prasad, K. Lipid metabolism in cancer: A systematic review. J. Carcinog., 2021, 20(1), 4. doi: 10.4103/jcar.JCar_15_20 PMID: 34321955
  41. Cai, L.; He, Y.; Huang, H. The role and mechanism of lycopene in regulating the PI3K/AKT pathway to inhibit epithelial-mesenchymal transition in ovarian cancer cells. Chin. Tradit. Herbal Drugs, 2022, (08), 1943-1948.
  42. Yao, Z.; Gao, G.; Yang, J.; Long, Y.; Wang, Z.; Hu, W.; Liu, Y. Prognostic role of the activated p-AKT molecule in various hematologic malignancies and solid tumors: A meta-analysis. Front. Oncol., 2020, 10, 588200. doi: 10.3389/fonc.2020.588200 PMID: 33363017
  43. Deng, S.; Leong, H.C.; Datta, A.; Gopal, V.; Kumar, A.P.; Yap, C.T. PI3K/AKT signaling tips the balance of cytoskeletal forces for cancer progression. Cancers, 2022, 14(7), 1652. doi: 10.3390/cancers14071652 PMID: 35406424
  44. Malek-Esfandiari, Z.; Rezvani-Noghani, A.; Sohrabi, T.; Mokaberi, P.; Amiri-Tehranizadeh, Z.; Chamani, J. Molecular dynamics and multi-spectroscopic of the interaction behavior between bladder cancer cells and calf thymus DNA with rebeccamycin: Apoptosis through the down regulation of PI3K/AKT signaling pathway. J. Fluoresc., 2023, 33(4), 1537-1557. doi: 10.1007/s10895-023-03169-4 PMID: 36787038
  45. Wang, Y.; Huang, Z.; Li, B.; Liu, L.; Huang, C. The emerging roles and therapeutic implications of epigenetic modifications in ovarian cancer. Front. Endocrinol., 2022, 13, 863541. doi: 10.3389/fendo.2022.863541 PMID: 35620395
  46. Ratovitski, E. Anticancer natural compounds as epigenetic modulators of gene expression. Curr. Genomics, 2017, 18(2), 175-205. doi: 10.2174/1389202917666160803165229 PMID: 28367075
  47. To, K.K.W.; Cho, W.C.S. Flavonoids overcome drug resistance to cancer chemotherapy by epigenetically modulating multiple mechanisms. Curr. Cancer Drug Targets, 2021, 21(4), 289-305. doi: 10.2174/1568009621666210203111220 PMID: 33535954
  48. Zając, A.; Sumorek-Wiadro, J.; Maciejczyk, A.; Langner, E.; Wertel, I.; Rzeski, W.; Jakubowicz-Gil, J. LY294002 and sorafenib as inhibitors of intracellular survival pathways in the elimination of human glioma cells by programmed cell death. Cell Tissue Res., 2021, 386(1), 17-28. doi: 10.1007/s00441-021-03481-0 PMID: 34236519
  49. Andreidesz, K.; Koszegi, B.; Kovacs, D.; Bagone, V.V.; Gallyas, F.; Kovacs, K. Effect of oxaliplatin, olaparib and LY294002 in combination on triple-negative breast cancer cells. Int. J. Mol. Sci., 2021, 22(4), 2056. doi: 10.3390/ijms22042056 PMID: 33669671
  50. Bai, J.; Xu, Y.; Dieo, Y.; Sun, G. Combined low-dose LiCl and LY294002 for the treatment of osteoporosis in ovariectomized rats. J. Orthop. Surg. Res., 2019, 14(1), 177. doi: 10.1186/s13018-019-1210-1 PMID: 31196133
  51. Yang, H.; Li, H.; Lu, S.; Shan, S.; Guo, Y. Fuzheng jiedu decoction induces apoptosis and enhances cisplatin efficacy in ovarian cancer cells in vitro and in vivo through inhibiting the PI3K/AKT/mTOR/NF-κB signaling pathway. BioMed Res. Int., 2022, 2022, 1-18. doi: 10.1155/2022/5739909 PMID: 35281608

Дополнительные файлы

Доп. файлы
Действие
1. JATS XML
Скачать

© Bentham Science Publishers, 2025